Alcohol abuse and dependence is a major health problem in the United States affecting over 13 million individuals and responsible for approximately 148 billion dollars in economic loss annually. The recent introduction of naltrexone, an opiate antagonist, has renewed interest in using pharmacotherapy as an effective adjunct in combination with the traditional behavioral therapy and coping-skills that are the mainstay of treatment. However, the benefits of opiate antagonists outside a few, well-controlled studies are unproven, and several recent studies have failed to demonstrate a beneficial effect of naltrexone on alcohol consumption. These failures are believed to be the result of study designs that do not adequately control for the high medication noncompliance rate in this population. In addition, other studies have shown that the benefits of naltrexone increase when compared to placebo if the subset of compliant naltrexone and placebo subjects is compared. Collectively, these studies indicate that obtaining the positive results of naltrexone on alcohol consumption in clinical practice will be difficult without some method of improving patient medication compliance. Therefore, the long-term goal of this project is to increase medication compliance in alcohol dependent patients. This will be achieved by developing an implantable, biodegradable, controlled-release, depot-delivery system for a model opiate antagonist. Medication compliance will be increased because the implanted dosage form will release the opiate antagonist at a controlled rate over an extended period, thereby obviating the need for daily medication administration. Nalmefene has been chosen as the opiate antagonist for this system, because its opiate receptor activity and pharmacokinetic disposition make it more suitable to the development of an implantable dosage than naltrexone. The objective of this proposal is to formulate a biodegradable pellet that will release nalmefene at a controlled rate over a one-month period. To achieve this goal, the first specific aim will be to formulate a nalmefene pellet with optimal release characteristics, and the second aim will be to model the pharmacokinetics of nalmefene after implantation of the pellet into rats. The results from this study will provide insight into the probable sustained plasma concentration of nalmefene that can be achieved from this dosage form, and the feasibility of developing a biodegradable nalmefene controlled-release implant for the clinical treatment of alcohol dependence.